The oral route of drug administration is the most commonly used. It is mainly due to its various advantages which include ease in the administration of the drug, economical production costs, possibility of self medication etc. This review therefore provides a brief insight into various drug formulations which are associated with the oral route of administration. Few of the most common oral drug formulations briefly described in this review includes tablets, capsules, liquids, granules, oral powders and oral sprays.
The most frequently used route for drug administration is the oral route. Furthermore, oral medications are considered as the first avenue in the development and discovery of various new pharmaceutical formulations and drug entities. This is mainly due to convince in administration, patient acceptance and the cost effective manufacturing process. Conventional immediate release formulations, for many drug substances provide effective therapy thereby maintaining the required equilibrium between pharmacodynamic and pharmacokinetic profiles with an acceptable level of safety to the patient. However for therapeutic agents which are unstable to various enzymes (in particular to proteolytic enzymes) and those which are poorly absorbed in the GI tract sometimes represent a limitation for the potential development of oral dosage forms. Hence, several physiological and pharmaceutical challenges (i.e. include physiochemical nature of the drugs, variability in GI environment such as presence of food & pH, along with the enzymatic activity within the alimentary canal etc play a role in frequently impairing the overall process of oral drug delivery (Augsburger et al., 2008).
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Once an immediate release dosage form (which is the most common) is orally administered, it initially disintegrates, dissolves in the GI fluids, crosses the GI mucosa, enters the mesenteric blood system & finally passes through the liver before it reaches the systemic circulation and the site of action (the below figure 1 shows this process) . During this whole transition process, the drug may be metabolized totally or partially by enzymes in the gut wall, GI fluids or by the hepatic metabolism before the drug even reaches the systemic circulation, thus consequently resulting in the net decreased bioavailability due to first-pass metabolism & metabolic formation of pharmacologically active species (David S. et al., 2008)
Figure 1: Shows how a drug (administered as a solid) faces several barriers and sites of loss in its movement during the GI absorption.
With regards to the oral route of administration following are some of the most common formulations associated with it:
ORAL ROUTE OF ADMINISTRATION
Tablets: It includes the following
? Conventional Compressed Tablets / Regular Tablets
? Multiple Compressed Tablets
? Chewable Tablets
? Water soluble Tablets /Effervescent
? Orodispersible Tablets
? Sublingual Tablets
? Buccal Tablets
? Coated Tablets
? Modified Release Tablets
Capsules: It includes the following
? Regular Capsules
? Modified Release Capsules
Liquids: It includes the following
? Oral Solutions
? Oral Syrups
? Mouthwashes And Gargles
Granules: It includes the following
? Bulk Granules
? Divided Granules
Oral Powders: It includes the following
? Bulk Powders
? Divided Powders
? Powders For Oral Liquids
Each of the above mentioned oral formulation can be discussed in detail as under:
Tablets are the most common oral dosage form and are mostly drug particles or powder compressed with tablet fillers. The formulation of tablets involves the use of various different components, each of which has its role to facilitate the manufacture or to control the biological performance of the dosage form.
Regular Tablets/ Conventional Compressed Tablets:
These tablets represent a significant proportion of the tablets that are clinically used and are designed to provide rapid disintegration & hence rapid drug release. Compression of granules or powders (both containing the drug) into the required geometry is one of the main processes involved in the manufacture of these tablets. Once the drug is ingested the tablet disintegrates within the GI tract, dissolves in the gastric fluid and finally gets absorbed systemically. These are the cheapest and easiest to make as they are not modified nor are they specially formulated to give any special characteristics. Examples Paracetamol, Citalopram etc (Starbrick , 2007)
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Multiple Compressed Tablets:
In short, these are the tablets which are composed of at least two layers. Multiple compressed tablets are mainly available in two designs i.e. multiple layered and compressed coated. In case of the multiple layered design the first layer is produced by a relatively light compression of the drug containing granules or powder mix. A next layer which is formed by compression of the granules or powder mix, containing the drug, is then mounted on the top of the lightly compressed first layer. In case of the compressed coated design the initial layer is prepared by light compression in a similar fashion as mentioned above, which is then removed & located in a second tablet press. This is followed by feeding of the powders or granules of the second coat into the press where a constant mass around the surface and edges of the pressed tablet is allowed to form prior to compression to form the finished product. At this stage it is important to mention that although it is possible to prepare tablets containing more than two layers, however in doing so the complexity of the manufacturing process in significantly increased (Augsburger et al., 2008).
As the name suggests these tablets are chewed within the buccal cavity before/prior swallowing. They are effective alternative for patients (children and adults) who have difficulty swallowing whole large tablets or capsules. Chewable tablets are usually prepared by the process of wet granulation and are not compressed very hard. Furthermore, the most commonly used base diluents in their preparation is mannitol, due to its pleasant texture & taste and due to the fact that it can effectively mask the taste of objectionable actives. They are often flavoured (to make they more palatable) & are easy to transport and can be taken without water. Examples include Gaviscon Tablets, Calcichew Tablets etc (Florence et al., 2009)
Effervescent tablets are dissolved in water before administration where they rapidly disintegrate. The process of tablet disintegration is due to a chemical interaction that occurs between two components i.e an organic acid (eg tartaric / citric acid) & alkali metal carbonates or bicarbonates in the presence of water. Hence the liberation of carbon dioxide from this reaction overall results in the tablet disintegration. Furthermore they are prepared by the heat fusion technique.
One of the main advantages of using effervescent tablets is the production of such a dosage form from which the therapeutic (active) agent is absorbed more rapidly than from an alternative solid-dosage forms e.g. conventional tablets thereby providing a rapid onset of action. On the other hand, one of the main disadvantage for such a type of oral dosage form is the possible unavailability of water and the need for special packaging. These tablets require a moisture-impermeable packaging, to inhibit the interaction between the organic acid and alkali metal carbonates due to the presence of environmental moisture. Examples include Aspirin & Paracetamol soluble tablets (Florence et al., 2009)
These tablets present a new approach to drug delivery & hence are required to be dissolved in the mouth (sucked) first and then swallowed. They are often sweetened and flavoured making them an attractive option for patients who have difficulty swallowing capsules/tablets. However the downside for these tablets is that they are more expensive in comparison to the conventional formulations (eg chewable, effervescent tablets etc) and the patients must have swallowing reflux in order to use these tablets. Examples include Zyprexa (Olanzapine) & Zoton (lansoprazole)
These are compressed tablets which are formulated without a disintegrant and must be sucked, allowing them to dissolve in the mouth. They are used either for local activity (throat/mouth lozenges) or for systemic effect (vitamins). Examples include Nystatin lozenges (David S. et al., 2008).
Sublingual & Buccal Tablets:
Both buccal and sublingual tablets are such oral dosage forms that are held within the oral cavity where they slowly dissolve. The type of tablet dictates the location within the oral cavity. For example Sublingual tablets are placed under the tongue where they dissolve slowly whereas Buccal tablets are placed between the cheek and the gingival. Both of these tablets produce immediate systemic effects by enabling the drug to be directly absorbed through the oral mucosa by preventing the first pass effect. These tablets are mainly used to enable systemic drug absorption where oral drug delivery is inappropriate e.g. nausea or where rapid drug absorption into the systemic circulation is required. E.g. Isoprenaline sulphate & Glyceryl trinitrate tablets. With regards to their physical appearance these tablets are small & flat, without a disintegrant and are lightly compressed to produce soft tablets. Examples for Sublingual tablets include Glyceryl trinitrate tablets whereas that for Buccal tablets include Buccastem (prochlorperazine) tablets (Augsburger et al., 2008).
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These can be sub-divided into three different categories
Enteric Coated Tablets:
These tablets are mainly used to prevent the drug from being inactivated or degraded by the gastric acid within the stomach or to protect the gastric mucosa of stomach from irritation. They are coated with a polymer that does not dissolves under acidic conditions i.e. within the stomach, however it dissolves under alkaline conditions (e.g. in the small intestine where pH is greater than 4). Few examples of polymers used in the production of these enteric coated tablets include methacrylic acid co-polymers, cellulose acetate butyrate etc. Examples of enteric coated tablets include Pantoprazole EC Tablets, Aspirin EC Tablets etc (David S. et al., 2008)
Sugar Coated Tablets
These mainly include conventional tablets which are coated with a concentrated sugar solution to either mask the bitter taste of the drug or to improve the appearance of the formulation. However in the past couple of years the use of sugar coated tablets has decreased due to the advent of film coated tablets. This is due to the better mechanical properties of the film coated tablets. Examples include FLUSIN & LEGALON 70 sugar coated tablets (Hunter, 2001).
Film Coated Tablets:
Film coated tablets are common conventional tablets which are either coated with a single or multiple mixture of polymers. Few examples of such polymers which are used to film coat and which dissolve in the stomach to facilitate both the process of tablet disintegration and drug dissolution include hydroxypropylcellose, Eudragit E100 etc. As mentioned early on that film coatings show better mechanical properties when compared to the sugar coatings therefore they may be deposited over embossed markings (on the tablet surface). However they are less elegant than sugar coated tablets. Examples of Film Coated Tablets include Metformin Film Coated Tablets (David S. et al., 2008)
Modified Release Tablets:
Dosage forms having drug release characteristics based on time & course, which are designed to accomplish convenience or therapeutic objectives that are not offered by conventional or immediate release dosage forms can all be collectively mushroomed under the term of modified release dosage forms. The ideal candidates for such dosage forms include drugs, used in the treatment of chronic conditions, with short half-lives (possessing a good therapeutic index and uniform absorption pattern). Modified release preparations can be of two different types i.e extended release or delayed release.
Delayed release dosage forms are designed in such a fashion so that all or portion of a drug is released at times much later than the time of administration. This delay may be environment specific or time based. Whereas on the other hand extended release dosage forms allow at least twice the reduction in the dosing frequency in comparison to conventional dosage form. Hence, most controlled release products are good examples of extended release dosage forms. These dosage forms can further be categorized on the basis of type of formulation & by their mechanism of release. Some other modified release dosage forms include targeted release and repeat action dosage forms. Examples of modified release dosage form includes Morphine Sulphate tablets M/R (Augsburger et al., 2008).
Capsules are solid dosage forms which are most commonly composed of gelatin. Gelatin is a substance of natural origin with unique properties and is one of the major components of the capsule. Gelatin is used because it has good film forming properties; it is non-toxic and is readily soluble in biological fluids at body temperature. Capsules are available in two typeÃ¯Â¿Â½s i.e. hard and soft gelatin capsules. These differ in both their capsule design and mechanical properties. Soft gelatin capsules are more flexible in comparison to the hard gelatin capsules and are composed of a one-piece capsule shell only whereas hard gelatin capsules are less flexible and are composed of two individual pieces i.e. the capsule and the body (Starbrick , 2007).
As the name states, these contain drugs (sometimes with other inert fillers) encapsulated in a gelatin capsule. Examples include Amoxicillin capsules
Modified Release Capsules:
These oral dosage forms are produced to either reduce the frequency of drug administration by extending the release pattern of the drug or are altered in such a manner to target specific sites within the gut. Examples include Adizem (Diltiazem) sustained release capsules, Dipyridamole modified release capsules (Hunter, 2001)
Liquid preparations in which the therapeutic agent and the various excipients dissolved in the chosen solvent system is referred to as pharmaceutical solution. They are used in situations where solid dosage forms e.g. tablets or capsules cannot be swallowed, however they are usually a more expensive alternative. Since they are easier to swallow therefore they are acceptable dosage forms for both pediatric and geriatric use. As the drug is in solution therefore it is readily available for absorption and hence the therapeutic response is faster. Solutions however have another drawback i.e. they are bulky and are inconvenient to transport. In addition to it, the stability of excipients (within the solutions) is poorer than in solids and they provide a suitable media for microbial growth too. Purified Water is widely used for most preparations (Florence et al., 2009)
Pharmaceutical solutions contain a variety of excipients, each of which has a defined pharmaceutical purpose. Some of the liquid formulation additives include buffers, colourants, flavouring agents and preservatives. Buffers are employed within pharmaceutical solutions to resist pH changes. The choice of buffer depends upon the pH and the buffering capacity. Most widely accepted buffers include carbonates, citrates, phosphates etc. With regards to colouring agents they are used for product identification and for attractiveness. Flavours on the other hand are added to mask the taste of the solution, thereby increasing the palatability. This is especially useful in case of pediatric formulations. Few examples of flavouring agents include fruit juices, peppermint oil, and methanol. Antioxidants help in the prevention of drug degradation in solution, examples of antioxidants include ascorbic acid, sodium metabisulphite etc. Finally as the name states, sweetening agents are used in liquid formulations to increase the palatability of the therapeutic agent. One of the most commonly used sweetening agent is sucrose due to its solubility in water and due to its stability at a wide range of pH. Other examples of sweeteners include liquid glucose, sorbitol, aspartame etc (David S. et al., 2008)
Types of Liquid Preparations:
These are administered to the GI tract to provide absorption of the therapeutic agent. As the GI environment is highly resilient, therefore it is possible to formulate oral solutions over a broad range of pH. The major excipients used in the preparation of oral solutions include buffers, preservatives, antioxidants, flavours and colours along with viscosity modifying agents. However in comparison to other oral preparations, in order for a formulation to be classified as a solution, all components within it (including the active agent) must be soluble i.e. with no sign of any precipitation (Hunter, 2001). Examples of oral solutions include Chlorpheniramine oral solution, Amitriptyline oral solution etc
These either consist of highly concentrated, sugar substitute (that traditionally contain a flavouring agent) or an aqueous solution of sugar. Examples include orange, raspberry syrup etc. Unflavoured syrups are also available which are made up of an aqueous solution containing up to 85 percent of sucrose. The active drug agent may either be added, as the syrup is being prepared or is directly incorporated into the system. The choice of syrup vehicle mainly depends upon the physiochemical properties of the active drug agent. However the major components of the syrup include purified water, sugar substitutes (artificial sweeteners) or sugar (sucrose), preservatives, flavours and colours. Example includes Diphenhydramine Oral Syrup (Florence et al., 2009)
Elixir refers strictly to solutions of potent or nauseating drugs containing alcohol as a co-solvent (60-70 percent). The concentration of alcohol required in the elixir is unique to each formulation and is important in insuring that all of the other vital components within the formulation remains within the solution. Moreover, the presence of alcohol in elixirs presents a possible problem for those adults who wish to avoid alcohol and in case of pediatric formulations. The main components of an elixir include purified water, alcohol, poly co-solvents, sweetening agents, flavours and colours. Examples include Flucloxacillin elixir, bropheniramine elixir etc
These are viscous preparations that consist of the active drug agent dissolved in a vehicle composed of a high percentage of sucrose (and if required) other sweetening agents. Due to the smoothing action of linctuses on the inflamed mucous membranes they are primarily employed in the treatment of cough. Furthermore, linctuses should not be diluted beforehand and should be sipped slowly. Example included Codeine Linctus (Starbrick , 2007)
Mouthwashes and Gargles:
These are aqueous solutions which are used for the treatment of infection and inflammation of the oral cavity. They usually contain analgesics, antiseptics and astringents. Apart from these other formulation components such as colours, preservatives, flavouring agents and sweetening agents are frequently required to improve the acceptability and the palatability of the preparation. These are sometimes used directly and sometimes are required to be diluted with warm water before use. Examples include Hydrogen peroxide, Chlorhexidine, Nystatin etc (Starbrick , 2007)
Suspensions are liquids which consist of insoluble solid particles dispersed throughout a liquid phase. Usually most of the suspensions are ready to use whereas some of them are prepared as solids to be reconstituted just before use. Strictly speaking, suspensions should be homogenous between the time of shaking and dispensing of the required dose. Therefore the suspended particles should be uniform sized and small to result in a smooth elegant product which is free from grittiness. Examples of suspensions include Co-amoxiclav suspension, Fluconazole suspension etc. (Florence et al., 2009)
Powder particles aggregated to form larger particles, can be termed as granules. They can be sub-divided into two different types i.e. bulk and divided
As they do not dissolve in water therefore they can either be washed down (without chewing) with plenty of liquid or can be mixed with liquid & swallowed immediately. One of the common examples of bulk granules include most of the bulk-forming laxatives. However some bulk granules are flavoured to increase palatability. Other examples of bulk granules include Isogel (ispaghula husk), Pancreatin BP etc.
These are granulated products consisting of individually wrapped single dose. The best candidate which can be formulated in such a way would include effervescent granules. Examples of divided granules include Colestid and Fybogel (Ram, 2007)
Oral powders can be defined as intimate mixtures of finely divided, dry drugs and chemicals (excipients) which are intended for oral administration. They can be sub categorized into the following three types
The mixed ingredients are usually packed into a suitable wide mouth container and contain non toxic constituents in relatively large doses. Example includes Magnesium Trisilicate oral powders.
They have similar formulation to bulk powders however single doses are individually packed. They have a longer shelf life in comparison to liquids and are portable. Most of the divided powders should be mixed with water before administration. Example include Questran and Movicol
For Oral Liquids (Solutions and Suspensions):
As it is known that many of the antibiotics are chemically and physically unstable when they are formulated as either suspensions or solutions, hence therefore, they are prepared as a dry powder. When required for use the dry powder is reconstituted with a given quantity of water prior to use. However once the preparation is produced, it has a very short shelf life. Examples include Augmentin co-amoxyclav suspensions, Diflucan etc.
In case of such oral formulation, the drug is available as a sublingual or as an oral spray, which produces very immediate effect due to the absorption of the drug from oral mucosa. Oral sprays are easy to transport and have a longer shelf life in comparison to buccal or sublingual tablets. Examples include Benzydamine spray, GTN spray (Ram, 2007).
To sum up, the oral route still remains the most favourite and major route for drug delivery. Despite its limitations and challenges, the oral products always rank the first in the list of pharmaceutical products (as they have greater therapeutic outcome and offer increased patient compliance). Each oral formulation discussed above have their own advantages and disadvantages & the choice to use a particular formulation depends in accordance to the patients need. In addition to it, at present, a combination of different formulation approaches (i.e. use of absorption enhancers, metabolism inhibitors , Halo drug delivery system etc) are being used to tackle the various drawbacks (first-pass metabolism, low bioavailability etc) associated with oral preparations, however they still need further research and development. Hence in short, the main goal for future oral preparations would be to optimize the drug delivery potential of this (oral route) by careful designing of the drug and its delivery system in such a way which takes into account various factors such as the metabolic & biological barriers to oral delivery, physicochemical properties of the drug and various patient related critical variables.